Drug-Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies

Abstract

Background and objectives: Darolutamide is a novel androgen receptor (AR) antagonist approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Accordingly, the drug-drug interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies.

Methods: In vitro studies were performed to determine the potential for darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP) isoforms, other metabolizing enzymes and drug transporters. A phase I drug-interaction study in healthy volunteers evaluated the impact of co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole [CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the pharmacokinetics of darolutamide. Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3].

Results: In vitro, darolutamide was predominantly metabolized via oxidative biotransformation catalyzed by CYP3A4 and was identified as a substrate for P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or slightly inhibited in vitro with darolutamide, and a rank order and mechanistic static assessment indicated that risk of clinically relevant DDIs via CYP inhibition is very low. In vitro, darolutamide exhibited no relevant induction of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1- and OATP1B3-mediated transport was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3 inhibition.

Conclusions: Darolutamide has a low potential for clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased exposure of BCRP and probably OATP substrates was the main interaction of note.

Fig. 1

Study design of the phase I clinical trials with a a strong CYP3A4/P-gp and BCRP inhibitor and a CYP3A4/P-gp inducer, b CYP3A4 and P-gp substrates and c a substrate for BCRP, OATP1B1, OATP1B3 and OAT3. ^aDosed in the morning on days 1–10, except for day 8 when subjects received a single dose of darolutamide 600 mg in the morning and rifampicin 600 mg 12 h later; ^bplasma and urine sampling to evaluate the PK of rosuvastatin; ^cplasma sampling to evaluate the PK of darolutamide, its diastereomers and keto-darolutamide. BCRP breast cancer resistance protein, BID twice daily, CYP cytochrome P450, DABE dabigatran etexilate, P-gp P-glycoprotein, PK pharmacokinetic(s), QD once daily

Fig. 2

Effects of comedications on the PK of darolutamide: changes in exposure parameters (a) and mean plasma concentration-time profiles for single-dose b darolutamide and c keto-darolutamide alone and with itraconazole or rifampicin in healthy male subjects (N = 15). PK pharmacokinetic(s)

Fig. 3

C_max and AUC of non-conjugated DABE and midazolam in the absence (day 1) and presence (day 9) of darolutamide. Data from treatment with DABE 1.5 h prior to darolutamide (period 2, day 3) are not presented as the results did not differ from those of period 2, day 9. AUC area under the concentration-time curve, C_max maximum observed drug concentration, DABE dabigatran etexilate

Fig. 4

Effects of darolutamide on the PK of other medications: changes in exposure. AUC area under the plasma concentration time curve, AUC_(0–24) AUC from time 0 to 24 h, BCRP breast cancer resistance protein, CI confidence interval, C_max peak concentration, CYP cytochrome P450, Pg-p P-glycoprotein, PK pharmacokinetic(s)

Fig. 5

Mean plasma concentration-time profiles of rosuvastatin in the presence and absence of darolutamide in healthy participants (N = 29). A single oral dose of rosuvastatin 5 mg was administered alone in treatment period 1, and a single dose of rosuvastatin 5 mg was administered on day 8 following multiple doses of darolutamide 600 mg BID in treatment period 2. This study included 15 males and 15 postmenopausal females; gender was not found to have a significant effect on pharmacokinetic parameters (data on file). BID twice daily, LLOQ lower limit of quantification (0.05 µg/l)